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PubMed1995

Pharmacokinetic, metabolic, and antidiarrheal properties of (D and L) heptapeptides of sorbin in rodent.

The C-terminal heptapeptide-amide (C7-sorbin) is the minimal biologically active fragment of sorbin inducing an increase in intestinal hydroelectrolytic absorption. An analogue (D7-sorbin), characterized by the replacement of the ultimate C-terminal amino acid L-alanine-amide by D-alanine-amide, was synthetized. For pharmacokinetic studies, D7-sorbin and C7-sorbin were tritium labeled. After IV injection, clearances were 10.6 and 30.2 ml-1 for D7-sorbin and C7-sorbin, respectively, and MRT were 34 and 18 min. After SC administration, Cmax attained 0.41% and 0.12% of the dose/ml, respectively. The IP route showed a 45-min delay before Cmax and a 100% bioavailability for both peptides. D7-sorbin was principally excreted in urine, as shown by balance study, and in part in intact form, as controlled by mass spectrometry. D7-sorbin induced a significant decrease of the VIP-induced ileal secretion, previously observed with C7-sorbin. The change of L-Ala to D-Ala increased the stability of the synthetic C-terminal peptide of sorbin whereas its biological activity, bioavailability, and route of elimination were unchanged.

Animals↗
PubMed2000

Effect of zaldaride maleate, an antidiarrheal compound, on intracellular cyclic nucleotide-mediated intestinal ion secretion in rats.

The purpose of this study is to clarify the mechanisms of action of zaldaride, a calmodulin inhibitor. 16,16-Dimethyl prostaglandin E(2), forskolin, 8-bromo cAMP, nitroprusside, 8-bromo cGMP and Escherichia coli heat-stable enterotoxin STa increased the short-circuit current in rat colonic mucosa. Zaldaride at >/=10 microM significantly attenuated the 16,16-dimethyl prostaglandin E(2) and Escherichia coli heat-stable enterotoxin STa-induced increase in short-circuit current; whereas it did not affect other secretagogues-induced effects. These results suggest that zaldaride inhibits the activation of Ca(2+)/calmodulin-sensitive adenylate cyclase or guanylate cyclase linked to a receptor.

16,16-Dimethylprostaglandin E2↗
PubMed1990

Potential antisecretory antidiarrheals. 2. Alpha 2-adrenergic 2-[(aryloxy)alkyl]imidazolines.

Lofexidine, an alpha 2-agonist, has central hypotensive activity and peripheral intestinal antisecretory activity. Analogues were synthesized with increased polarity in an attempt to prevent penetration of the blood-brain barrier. The compounds were evaluated in the cholera toxin treated ligated jejunum of the rat and in the Ussing chamber with a rabbit ileum preparation. Active compounds were determined to be alpha 2-adrenergic agonists by yohimbine reversals of their Ussing chamber activities. The 2,6-dimethyl derivative of lofexidine, 4a, was as active as lofexidine in vivo, but derivatives with 2,6-substituents larger than ethyl were inactive. (Aryloxy)alkyl derivatives which have an imidazoline and a methyl or larger group as part of the alkyl exhibited the best antisecretory activity. Compounds with substituents in the para position of the phenyl ring were generally inactive. 3-Amino-2,6-dimethyl derivative 21 was twice as active as 4a. A 2-methyl substituent is required in the 3-amino series to retain good activity. 2-Methyl derivative 12a had activity comparable to that of 4a, while 6-methyl derivative 12f was inactive. Substituents on the 3-amino group did not affect the activity, but substituting a hydroxyl for the amino group produced an inactive compound. Replacing the phenyl moiety with a 4-indole resulted in retention of activity, but other heterocycles were inactive. Compound 12a was resolved and d isomer 32 was five times more potent than l isomer 33. The more active compounds in the rat cholera toxin assay (RCTA), when evaluated in the dog, exhibited antisecretory activity but also exhibited central nervous system (CNS) effects, sedation and ataxia, at 10 mg/kg, and in spontaneously hypertensive rats at 50 mg/kg. A measure of polarity, log P, was calculated for the (aryloxy)alkyl groups. Regression analysis showed no correlation of antisecretory ED50 to the calculated log P. The active compounds did not show a separation of the central CNS effects from the peripheral antisecretory activity by increasing the polarity.

Adrenergic alpha-Agonists↗
PubMed1976

3,3-Diphenyl-3-(2-alkyl-1,3,4-oxadiazol-5-yl)propylcycloalkylamines, a novel series of antidiarrheal agents.

A series of 4-amino-2,2-diarylbutyronitriles (3) prepared for testing as inhibitors of gastrointestinal propulsive activity did not show any enhancement over such existing agents as diphenoxylate and loperamide. However, conversion of the nitrile group to a 2-methyl-1,3,4-oxadiazol-5-yl function led to compounds 5g and 5j, statistically equipotent to diphenoxylate and loperamide in the mouse and showing a very low order of analgesic activity. Structural modifications determined that the best separation of antipropulsive and analgesic effects was obtained when the amino group was bicyclic and the oxadiazole ring had a 2-methyl substituent. The most potent compounds were and analogues of diphenoxylate and loperamide where the oxadiazole ring was present, but these compounds had marked analgesic activity.

Amines↗
PubMed1988

Potential antisecretory antidiarrheals. 1. Alpha 2-adrenergic aromatic aminoguanidine hydrazones.

Guanabenz, a centrally acting antihypertensive agent, has been shown to have intestinal antisecretory properties. A series of aromatic aminoguanidine hydrazones was made in an effort to separate the antisecretory and cardiovascular activities. Benzaldehyde, naphthaldehyde, and tetralone derivatives were synthesized. The compounds were evaluated in the cholera toxin treated ligated jejunum of the rat and in the Ussing chamber using a rabbit ileum preparation. A number of compounds, including members of each structural class, were active upon subcutaneous administration in the rat. Active compounds were determined to be alpha 2-adrenergic agonists by yohimbine reversals of their Ussing chamber activities. The compound displaying the best separation of activities was the aminoguanidine hydrazone of 2,6-dimethyl-4-hydroxybenzaldehyde (20).

Adrenergic alpha-Agonists↗
PubMed2003

Racecadotril versus loperamide: antidiarrheal research revisited.

Racecadotril is an enkephalinase inhibitor, presented as a purely antisecretory agent with advantages over the opiate-receptor agonist loperamide in the treatment of diarrhea. A critical review of the literature and the models used was performed. Although pretreatment with high doses of racecadotril reduced cholera toxin-induced secretion and although clinical efficacy was demonstrated in young infants--a population characterized by 10-fold higher plasma enkephalin concentrations compared with adults, the analysis calls into question the peripheral antisecretory selectivity and relative clinical efficacy. Conversely, loperamide can be proposed as an antisecretory agent at therapeutic concentrations. Its efficacy is well established in acute and chronic diarrhea. Current experimental and clinical comparative studies of both drugs have problems with regard to the selection of the doses, the validity of models, and/or the trial design. The conclusion is that more research is needed before reliable conclusions can be drawn on the place of racecadotril in diarrhea treatment.

Adolescent↗
PubMed1980

Dependence liability of two antidiarrheals, nufenoxole and loperamide.

We compared the dependence liabilities of therapeutic doses of nufenoxole and loperamide. Ten subjects received 10 mg nufenoxole every 12 hr for 10 days, and 9 others received 4 mg loperamide every 12 hr for 10 days. On the eighth day of drug a sensitive single-blind intravenous naloxone challenge was used to assess dependence liability. After 0.2, 0.4, and 0.6 mg naloxone, pupillary constriction (0.618 to 0.540 cm, p less than 0.005) was measured in subjects receiving nufenoxole, whereas slight dilation (0.596 to 0.622 cm, p less than 0.05) was observed in those receiving loperamide. Trapezius electromyogram activity decreased by 30% for nufenoxole and 12% for loperamide. There were slight decreases in core and skin temperatures (0.06 degrees to 0.12 degrees) in both groups, partly attributable to experimental conditions. Changes in physiologic measurements after naloxone were similar in both groups and not of sufficient importance to suggest physical dependence liability for either loperamide or nufenoxole at the doses used.

Adult↗
PubMedDate not supplied

Lack of oncogenicity of wood creosote, the principal active ingredient of Seirogan, an herbal antidiarrheal medication, in Sprague-Dawley rats.

Seirogan, an herbal medicine containing wood creosote (tablets, 10.0% w/w), has been developed and marketed for almost a century in various countries for the control of acute diarrhea and treatment of associated symptoms, such as abdominal cramping. Wood creosote (CAS no. 8021-39-4) is a mixture of simple phenolic compounds, including guaiacol and creosol and related compounds, and is chemically distinct from, and should not be confused with, coal tar creosote, a known carcinogen. In the current study, the oncogenic potential of wood creosote was assessed in a 96/103-week oral gavage study in Sprague-Dawley rats. Groups of 60 rats/sex received wood creosote at dose levels of 20, 50, or 200 mg/kg body weight [bw]/day. An additional group of rats received the vehicle, 0.5% carboxymethylcellulose in deionized, distilled water, at the same dose volume as the treatment groups (10 ml/kg) and served as the controls. Treatment-related decreases in survival, body weight, and food consumption, as well as increased incidences of clinical signs that included rales, decreased activity, and salivation, were noted at 200 mg/kg bw/day when compared with the control group. There was an increased incidence of reddened and edematous lungs in rats from the 200 mg/kg bw/day group that died during the study. The lung findings were suggestive of test article aspiration during dose administration or agonal aspiration preceding and possibly resulting in death, especially because these observations were not seen in animals that survived to scheduled sacrifice. Additionally, phenols are generally recognized as having corrosive properties. There were no changes in clinical pathology and no increases in neoplastic or non-neoplastic lesions, excluding the lung findings, related to treatment with wood creosote at any dose level. Although the results of this study indicate that the maximum tolerated dose of wood creosote was met or exceeded at 200 mg/kg bw/day, there was no evidence of oncogenicity at any dose level. The lack of any evidence of oncogenicity supports the safety profile of the active ingredient in Seirogan, wood creosote.

Animals↗
PubMed1985

Evaluation of BW942C, a novel antidiarrheal agent, against enterotoxins of Escherichia coli and Vibrio cholerae.

BW942C, an enkephalin-like pentapeptide with anti-diarrheal activity, was tested against crude toxins of Escherichia coli and Vibrio cholerae in the Y-1 adrenal cell assay, rabbit ileal loop assay, and suckling mouse assay. The effects of BW942C on in vitro ion transport were measured in rabbit ileum mounted in Ussing chambers. In vitro, BW942C decreased basal short-circuit current (2.26 and 3.15 mueq cm-2 h-1 in experimental samples and controls, respectively; n = 7, P less than 0.05) and increased basal net Cl absorption (1.59 and 0.50 mueq cm-2 h-1 in experimental samples and controls, respectively; P less than 0.025). Net Na absorption was also increased, but not significantly. BW942C did not block the secretory response to a maximal dose of purified heat-stable toxin. BW942C directly enhanced intestinal fluid absorption. In the Y-1 adrenal cell assay, 5 mg of BW942C per ml inhibited the cytopathic effect caused by cholera toxin or heat-labile enterotoxin of E. coli. In the rabbit ileal loop assay, E. coli heat-stable toxin, E. coli heat-labile enterotoxin, and cholera toxin were inhibited 35 to 70% by administration of BW942C. With the suckling mouse model, the fluid accumulation caused by E. coli heat-stable toxin was ablated by prior treatment with BW942C. The drug is currently being evaluated in patients with acute secretory diarrhea to determine its effect on clinical symptoms.

Animals↗
PubMed2000

The effect of zaldaride maleate, an antidiarrheal compound, on acetylcholine-induced intestinal electrolyte secretion.

The effect of zaldaride on acetylcholine-induced colonic electrolyte secretion was examined. The short-circuit current response to acetylcholine was partially reduced by tetrodotoxin, a neuronal blocker, and was completely inhibited by atropine, an acetylcholine M receptor antagonist, in the rat colonic preparations. The tetrodotoxin sensitive effect was significantly inhibited by zaldaride, whereas the tetrodotoxin insensitive effect was not affected. Acetylcholine release from synaptosomes of submucosal nerves of guinea-pig colon was significantly reduced by zaldaride. Zaldaride may reduce colonic electrolyte secretion by acetylcholine due to the inhibition of acetylcholine release from synaptosomes of colonic submucosal nerves.

Acetylcholine↗
PubMed1999

Effect of zaldaride maleate, an antidiarrheal compound, on visceral pain reflex induced by small intestinal distention in anesthetized rats.

Using distention of the small intestine as a visceral pain model, we investigated the effect of zaldaride maleate (ZAL), a selective inhibitor of calmodulin, on the depressor response. In pentobarbital-anesthetized rats, small intestine distention was induced by rapid application of intraluminal pressures of 40 cmH2O causing a reflex fall in arterial blood pressure. The depressor response to intestinal distention was abolished by intraperitoneal administration of capsaicin (5 mg/rat), which depletes neuropeptides such as substance P from the sensory neurons, on the mesenteric stalk and by neonatal pretreatment with capsaicin (50 mg/kg, s.c.). Morphine (20 mg/kg, s.c.) reduced the depressor response following intestinal distention. At doses of 3 mg/kg (i.v.) and higher, ZAL significantly reduced depressor response. The effect of morphine was reversed by naloxone (5 mg/kg, i.v.); the effect of ZAL was not affected. These results suggest that ZAL helps reduce the visceral pain induced by noxious stimulus and that the antinociceptive effect of ZAL is not mediated by opioid receptors.

Adrenergic alpha-Antagonists↗